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Microsecond Time-Scale Conformational Exchange in Proteins: Using Long Molecular Dynamics Trajectory To Simulate NMR Relaxation Dispersion Data

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journal contribution
posted on 08.02.2012 by Yi Xue, Joshua M. Ward, Tairan Yuwen, Ivan S. Podkorytov, Nikolai R. Skrynnikov
With the advent of ultra-long MD simulations it becomes possible to model microsecond time-scale protein dynamics and, in particular, the exchange broadening effects (Rex) as probed by NMR relaxation dispersion measurements. This new approach allows one to identify the exchanging species, including the elusive “excited states”. It further helps to map out the exchange network, which is potentially far more complex than the commonly assumed 2- or 3-site schemes. Under fast exchange conditions, this method can be useful for separating the populations of exchanging species from their respective chemical shift differences, thus paving the way for structural analyses. In this study, recent millisecond-long MD trajectory of protein BPTI (Shaw et al. Science 2010, 330, 341) is employed to simulate the time variation of amide 15N chemical shifts. The results are used to predict the exchange broadening of 15N lines and, more generally, the outcome of the relaxation dispersion measurements using Carr–Purcell–Meiboom–Gill sequence. The simulated Rex effect stems from the fast (∼10–100 μs) isomerization of the C14–C38 disulfide bond, in agreement with the prior experimental findings (Grey et al. J. Am. Chem. Soc. 2003, 125, 14324).

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